Clinical Trials /

Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer

NCT02457910

Description:

This partially randomized phase Ib/II trial studies the side effects and best dose of taselisib when given together with enzalutamide and to see how well they work in treating patients with androgen receptor positive triple-negative breast cancer that has spread to other places in the body. Taselisib is a PI3K inhibitor. The PI3K pathway is involved is cancer growth. Androgen may cause the growth of tumor cells. Enzalutamide may stop the growth of tumor cells by blocking the androgen receptor from working. Giving taselisib with enzalutamide may be a better treatment for patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Taselisib</span> and <span class="go-doc-concept go-doc-intervention">Enzalutamide</span> in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer
  • Official Title: A Phase Ib/II Trial of Taselisib (GDC-0032), a PI3K Inhibitor, in Combination With Enzalutamide in Patients With Androgen Receptor Positive Triple Negative Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02457910

    ORG ID: VICC BRE 1374

    NCI ID: NCI-2015-00795

    Trial Conditions

    Estrogen Receptor Negative

    Estrogen Receptor Positive

    HER2/Neu Negative

    Progesterone Receptor Negative

    Progesterone Receptor Positive

    Stage IV Breast Cancer

    Triple-Negative Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Enzalutamide ENZALUTAMIDE, MDV3100, Xtandi Arm I (taselisib, enzalutamide), Arm II (enzalutamide)
    Taselisib GDC-0032, TASELISIB Arm I (taselisib, enzalutamide), Arm II (enzalutamide)

    Trial Purpose

    This partially randomized phase Ib/II trial studies the side effects and best dose of
    taselisib when given together with enzalutamide and to see how well they work in treating
    patients with androgen receptor positive triple-negative breast cancer that has spread to
    other places in the body. Taselisib is a PI3K inhibitor. The PI3K pathway is involved is
    cancer growth. Androgen may cause the growth of tumor cells. Enzalutamide may stop the
    growth of tumor cells by blocking the androgen receptor from working. Giving taselisib with
    enzalutamide may be a better treatment for patients with breast cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the safety and tolerability of taselisib given in combination with
    enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of
    treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib
    given in combination with enzalutamide: Determination of the maximally tolerated dose (MTD)
    of taselisib given in combination with enzalutamide. (Phase Ib) III. To evaluate the
    efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + taselisib in
    patients with androgen receptor positive (AR+) triple negative (TN) metastatic breast cancer
    (MBC). (Phase II)

    SECONDARY OBJECTIVES:

    I. To determine the progression free survival (PFS) of enzalutamide + taselisib in patients
    with AR+ TN MBC.

    II. To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+
    TN MBC.

    TERTIARY OBJECTIVES:

    I. To explore predictors of biomarker response and mechanisms of resistance based on
    exploratory analysis of tumor tissue obtained through biopsies.

    II. Levels of phosphatase and tensin homolog (PTEN) expression by immunohistochemistry (IHC)
    and quantitative real-time polymerase chain reaction (qPCR).

    III. Presence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic
    subunit alpha (PIK3CA) gene.

    IV. Human epidermal growth factor receptor 2 (HER2) (IHC, fluorescence in situ hybridization
    [FISH]) and estrogen receptor (ER)/progesterone receptor (PR) levels (IHC) in tumor biopsy
    from a metastatic site.

    V. Levels of mitogen-activated protein kinase kinase (MEK) activity measured by
    phosphorylated extracellular-signal-regulated kinases (p-ERK1/2) (IHC) and phosphorylated
    p-ribosomal protein S6 (S6) (S235/236 and S240/244) at baseline and upon progression of
    disease.

    VI. Levels of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (p-AKT) (IHC) at
    baseline and upon progression of disease.

    VII. Gene expression profiling to assign a triple negative subtype. VIII. Whole exome
    deoxyribonucleic acid (DNA)-sequencing (seq) on DNA isolated at baseline and upon
    progression.

    IX. Plasma for circulating tumor DNA (ctDNA) analysis to assess PIK3CA mutation status in
    response and resistance.

    X. To assess the predictive effects of PIK3CA mutations and PTEN loss on PFS and CBR.

    XI. To evaluate the ability of multi-parametric magnetic resonance imaging (MRI) performed
    early in therapy to predict both biological and clinical response.

    OUTLINE: This is a phase Ib, dose-escalation study of taselisib followed by a randomized
    phase II study.

    PHASE IB: Patients receive taselisib orally (PO) once daily (QD) on days 1-28 and
    enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses
    repeat every 28 days in the absence of disease progression or unacceptable toxicity.

    PHASE II: Patients are randomized to 1 of 2 treatment arms.

    ARM I: Patients receive taselisib PO QD and enzalutamide as in Phase Ib. Courses repeat
    every 28 days in the absence of disease progression or unacceptable toxicity. Patients
    experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib.

    ARM II: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in
    the absence of disease progression or unacceptable toxicity. Upon disease progression,
    patients may crossover to Arm I.

    After completion of study treatment, patients are followed up for 30 days and then every 3
    months for 3 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (taselisib, enzalutamide) Experimental Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. Enzalutamide, Taselisib
    Arm II (enzalutamide) Active Comparator Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may crossover to Arm I. Enzalutamide, Taselisib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must provide informed written consent

    - Eastern Cooperative Oncology Group (ECOG) performance status 0-1

    - Clinical stage IV invasive mammary carcinoma

    - For phase 1b: HER2 negative, as defined for phase II; any ER/PR (negative or
    positive) can be enrolled in the phase 1b portion

    - For phase II: ER negative (defined as expression of ER in =< 1% cells), PR negative
    (defined as expression of PR in =< 1% cells), HER2 negative (acceptable methods of
    HER2 analysis include IHC [0, 1+], fluorescence in situ hybridization [FISH] with
    HER2/centromere on chromosome 17 [CEN17] ratio < 2, and/or chromogenic in situ
    hybridization [CISH] with HER2/CEN-17 ratio < 2), as previously documented by
    histological analysis

    - Androgen receptor positivity, defined as >= 10% of tumor cell nuclei with
    immunoreactivity for AR on central review at Vanderbilt

    - Measurable or bone-only evaluable disease; measurable disease is defined as at least
    one lesion that can be accurately measured in at least one dimension by Response
    Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, with radiologic scans
    within 21 days of day 1, cycle 1

    - Any number of prior therapies as long as patients have adequate performance status
    and meet all other eligibility criteria

    - Prior treatment with anti-androgens other than enzalutamide is acceptable

    - Phase 1b only: Formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue
    from the original diagnosis or the metastatic setting should be located; tissue must
    be submitted with 3 weeks of study initiation

    - Phase II only: Biopsy of a metastatic lesion in patients with reasonably accessible
    metastatic lesions (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast,
    bones, lung, and liver metastases); if a reasonably accessible metastatic lesion is
    not available, the patient may go on study provided that archived tissue is
    available; however, if a reasonably accessible site is available for biopsy, the
    patient must agree to biopsy; any patients not undergoing biopsy must be approved for
    study enrollment by the Protocol Chair; biopsies may be done with local anesthesia or
    intravenous conscious sedation, according to institutional guidelines; if a biopsy
    requires general anesthesia, then it is only allowed if acquisition of tissue is
    clinically indicated, and excess tissue may be collected for research purposes;
    patients without sites available for biopsy must have available tissue (archived
    formalin-fixed paraffin embedded blocks [FFPB] or fresh frozen tissue from original
    diagnosis or metastatic setting) for correlative studies; tissue needs to be located
    and available at the time of registration (tissue needs to be submitted within 3
    weeks of study initiation)

    - Absolute neutrophil count (ANC) >= 1500/mm^3

    - Platelet count >= 75,000/mm^3

    - Hemoglobin (HgB) >= 9 g/dL

    - Creatinine =< 1.5 X upper limits of normal (ULN)

    - Total serum bilirubin =< 1.5 x ULN (in patients with known Gilbert syndrome, a total
    bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (or =<
    5.0 x ULN if hepatic metastases are present)

    - For patients without known type II diabetes, the following is required at screening:

    - Fasting plasma glucose =< 160 mg/dL (7.49 mmol/L) and glycosylated hemoglobin
    (HbA1c) < 7.5 % or International Federation of Clinical Chemistry (IFCC) < 53
    mmol/mol

    - For patients with type II diabetes receiving only oral anti-hyperglycemic therapy
    (patients receiving insulin are not eligible), the following are required at
    screening:

    - HbA1c < 8.5 % or IFCC < 69.4 mmol/mol

    - Stable regimen of oral anti-hyperglycemic therapy without insulin usage for at
    least 3 weeks prior to first study treatment

    - Fasting plasma glucose levels =< 160 mg/dL (8.88 mmol/L) and no hypoglycemia
    (blood sugar [BS] < 60) during home monitoring for at least 1 week prior to
    study entry

    - Patients must be able to swallow and retain oral medication

    - For patients who are not postmenopausal or surgically sterile (absence of ovaries
    and/or uterus), agreement to remain abstinent or to use two adequate methods of
    contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal
    ligation), during the treatment period and for at least 30 days after the last dose
    of study treatment or 3 months after discontinuation of taselisib and/or
    enzalutamide, whichever is longer; hormone based oral contraceptives are not allowed
    on study; postmenopausal is defined as:

    - Age >= 60 years

    - Age =< 60 years and amenorrheic for 12 months in the absence of chemotherapy,
    tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone
    and estradiol in the postmenopausal range

    - Patients may have received radiation therapy to painful bone metastases or areas of
    impending bone fracture as long as radiation therapy is completed >= 2 weeks prior to
    day 1 of cycle 1 of treatment; patients who have received prior radiotherapy must
    have recovered from toxicity (=< grade 1) induced by this treatment; baseline
    radiologic scans must be obtained after completion of radiation

    - Patients must complete all screening assessments

    Exclusion Criteria:

    - Any kind of malabsorption syndrome significantly affecting gastrointestinal function,
    including history of Crohn's disease or inflammatory bowel disease

    - Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
    immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in
    the protocol; patients must have discontinued the above cancer therapies for 1 week
    prior to the first dose of study medication, as well as recovered to baseline from
    toxicity induced by previous treatments; any investigational drugs should be
    discontinued 2 weeks prior to the first dose of study medication and radiotherapy
    must have been completed >= 2 weeks prior to initiation of study drug (cycle 1, day
    1)

    - Prior use of PI3K or Akt inhibitors in the metastatic setting for the treatment of
    cancer; these include, but are not limited to: taselisib, GDC-0941, GDC-0980, BEZ235,
    BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126, PX-866, D-87503, D-106669,
    GSK615, CAL101; patients who have received PI3K/Akt inhibitors previously for < 4
    weeks will be eligible

    - Prior treatment with enzalutamide

    - Current or previously treated brain metastasis or active leptomeningeal disease; head
    imaging is required during screening in all patients to exclude the presence of
    central nervous system (CNS) metastatic disease

    - History of seizure or any condition that may predispose to seizure; history of loss
    of consciousness or transient ischemic attack within 12 months before day 1

    - Pregnant or lactating women

    - Insulin-dependent diabetes; patients with type II diabetes must meet the inclusion
    criteria outlined above

    - Uncontrolled intercurrent illness including, but not limited to:

    - Ongoing or active infection requiring parenteral antibiotics

    - Impairment of lung function (chronic obstructive pulmonary disease [COPD] >
    grade 2, lung conditions requiring oxygen therapy) or current dyspnea at rest

    - Symptomatic congestive heart failure (class III or IV of the New York Heart
    Association classification for heart disease)

    - Known left ventricular ejection fraction (LVEF) < 50%

    - Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within
    6 months

    - Uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic
    blood pressure > 100 mm Hg, found on two consecutive measurements separated by a
    1 or 2-week period despite adequate medical support)

    - Clinically significant cardiac arrhythmia (multifocal premature ventricular
    contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic
    or requires treatment [National Cancer Institute-Common Terminology Criteria for
    Adverse Events, version 4.0, grade 3])

    - Corrected QT using the Fridericia correction formula (QTcF) >= 480 msec on
    screening electrocardiogram (EKG)

    - Known history of QT/correct QT (QTc) prolongation or Torsades de Pointes (TdP)

    - ST depression or elevation of >= 1.5 mm in 2 or more leads

    - Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE)
    grade 2

    - Active autoimmune disease that is not controlled by nonsteroidal or steroidal (<
    10 mg of prednisone per day) anti-inflammatory drugs or active inflammatory
    disease, including small or large intestine inflammation such as active Crohn's
    disease or ulcerative colitis, which requires immunosuppressive therapy

    - Psychiatric illness/social situations that would compromise patient safety or
    limit compliance with study requirements including maintenance of a
    compliance/pill diary

    - Known history of chronic liver disease including cirrhosis, current alcohol
    abuse, or infection with hepatitis B virus or hepatitis C virus (active or
    carrier) or renal failure

    - Known history of chronic pancreatitis

    - Conditions that affect lymphocyte counts, such as human immunodeficiency virus
    (HIV) infection or immunosuppressive therapy

    - Use of prohibited drugs

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Clinical Benefit Rate (CBR) - Phase II

    Maximum Tolerated Dose (MTD) - Phase I

    Secondary Outcome Measures

    Overall Progression-Free Survival (PFS)

    Overall response rate (ORR)

    Cmax, the peak plasma concentration of taselisib after administration of taselisib

    Cmax, the peak plasma concentration of taselisib and enzalutamide after administration of both drugs

    Trial Keywords